DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05 May, 2026 has been entered.
Priority
The instant application, filed on 28 July, 2023, claims domestic benefit to US provisional applications no. 63/509,136 filed on 20 June, 2023 and no. 63/393,350 filed on 29 July, 2022.
Status of Application
The response filed on 11 May, 2026 has been entered in full. The response is amendment to a Final Rejection to the claim set filed on 10 March, 2026. In the amendment, claims 1, 2, 56, And 57 are amended, claims 5, 10, 13, 14, 15, 18, 19, 22, 26, 28, and 54 are previously presented, and claims 3, 4, 6-9, 11, 12, 16, 17, 20, 21, 23-25, 27, 29-53, 55, 58-103 are canceled. Therefore, claims 1, 2, 5, 10, 13-15, 18, 19, 22, 26, 28, 54, 56, and 57 are pending and are the subject of this office action.
Status of Objections and Rejections
In the office action of 04/20/2026
Claims 6-9 were rejected under 35 U.S.C. 103 over Valamehr in view of Morgan. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 1, 2, 5, 10, 13-15, 18, 19, 22, 26, 28, 54, 56, and 57 were rejected under 35 U.S.C. 103 over Valamehr and Morgan. The amendment of these claims requires a modified form of the 103 rejection over Valamehr in view of Morgan, Meissner, and Baumgartner and their rejection is maintained.
Claims are 1, 15, 18, 28, 56, and 57 have been rejected under a new rejection on the grounds of new nonstatutory double patenting over claim U.S. Patent No. 12,577,283 in view of Valamehr et al., Morgan et al., Meissner et al., and Baumgartner et al.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 5, 10, 13, 14, 18, 19, 22, 26, 28, 54, 56, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Valamehr et al. (WO 2021/071962) in view of Morgan et al. (2020) Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells Front. Immunol 11:1965 (hereafter Morgan), Meissner et al. (US Pat No: 10,968,426; 04/06/2021), and Baumgartner et al. (US 2025/0179481, priority date 06/01/2021).
In regards to instant claims 1, 2, and 15 Valamehr teaches a derivative effector cell (defined in the specification as including, immune cells (page 50, paragraph 000159) comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR (genetic modification) and optionally one or more modifications. These modifications include the (iii) knockout in one or both CD58 and CD54 and (viii) deletion or reduced expression in at least one of a list of genes which includes RFX5 and NLRC5 (of instant claim 15) (claim 41). Further Valamehr discusses HLA class II deficiency can be achieved by functional deletion or reduction of HLA-II associated genes including, not being limited to, RFXANK, CIITA, RFX5, and RFXAP (pg. 62, paragraph 000183) and CD58 knockout has a higher efficiency in reducing allogenic NK cells activation than CD54 knockout (pg.63, lines 6-7).
In regards to instant claims 5 and 10, Valamehr teaches a derivative effector cell comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR (Claim 41). Further Valamehr teaches the antigen recognition domain can be selected from a list which includes CD70 (claim 14).
In regards to instant claim 13, Valamehr teaches the derivative effector cell derived from a differentiated genetically engineered iPSC cell comprising the CAR of Claim 1 (Claim 41), and claim 1 of Valamehr further teaches the CAR when comprised in an iPSC promotes differentiation of the iPSC to a derivative effector cell and the iPSC derived effector cell has at least one of a list of characteristics which includes (iv) increased resistance to allorejection.
In regards to instant claim 14, Valamehr teaches resistance against alloreactive immune cell rejection wherein the alloreactive immune cell rejection is alloreactive T Cell mediated and/or alloreactive NK cell mediated, by reduced or eliminated HLA-I or HLA-II expression (pg.62, paragraph 000183). This is evidenced by Morgan which teaches important conditions of “off the shelf” immune cells include avoidance of rejection due to recognition by host T cells via HLA class I molecules or host NK cells by HLA class II receptors (pg.4, col 1, lines 24-27) and a lack alloreactivity to limit unwanted toxicities due to recognition and destruction of healthy host tissue. Further, Morgan teaches “veritable “off-the-shelf” cell therapeutics will likely require genetic engineering strategies that address multiple layer of immune recognition patterns and cytotoxic mechanism” (pg.4, col 1 lines 37-39). Thus, the teachings of Valamehr teach the development of an immune cell which is resistant to T-cell and/or NK-cell mediated alloreactive immune cell rejection.
In regards to instant claims 18 and 19, Valamehr teaches a derivative effector cell comprising a CAR and optionally one or more edits which can result in a list of modifications. These modifications include the (ii) β2m null or low expression in comparison to its counterpart primary cell (claim 41). Due to it being optional Valamehr teaches both a derivative effector cell with both modified or unmodified β2m expression.
In regards to instant claim 22, Valamehr teaches derivative effector cell comprising a CAR, and optionally one or more edits which can result in a list of modifications. These modifications include the (ii) β2m null or low expression in comparison to its counterpart primary cell, (iii) knockout in one or both CD58 and CD54, and (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5 and RFX5 (claim 41). Valamehr also teaches that HLA class I deficiency can be achieved by deletion or reducing the expression level of HLA class-I associated genes including, not being limited to, β2M gene, TAP1 gene, TAP2 gene, and Tapasin and HLA class II deficiency can be achieved by functional deletion or reduction of HLA-II associated genes including, not being limited to, RFXANK, CIITA, RFX5, and RFXAP (page 62, paragraph 000183). Valamehr further teaches that an iPSC and its
derivative cells with both HLA-I and HLA-II deficiency enable allogeneic cell therapies by eliminating the need for MHC (major histocompatibility complex) matching (page 62, paragraph 000183). Therefore, knockdown of both HLA-I and HLA-II together or independently is encompassed in claim 41 of Valamehr.
In regards to instant claim 26, Valamehr teaches a cell or population thereof wherein the cell comprises at least one CAR (claim 19) and further wherein teaches the cell or population thereof of claim 19 can comprise the (iii) knockout in one or both CD58 and CD54 and (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5 and RFX5 (claim 21). Valamehr also teaches an exogenous polynucleotide integration into the locus of a TCRa gene to knockout the expression of the gene (Claim 34).
In regards to instant claim 28, Valamehr teaches a cell or population thereof wherein the cell is an immune cell from a primary source (pg.33, lines 23-25).
In regards to instant claim 54, Valamehr teaches a method of manufacturing a derivative effector cell comprising a CAR, wherein the derivative effector cell is derived from a differentiated genetically engineered iPSC, and the iPSC comprises a polynucleotide encoding the CAR and optionally one or more edits resulting genomic modifications.
In regards to instant claims 56 and 57, Valamehr teaches a therapeutic use of the composition of claim 35 by introducing the subject suitable for adoptive cell therapy, further claim 35 refers to a composition comprising the cell or population thereof of claim 21, which refers to a derivative effector comprises at least one CAR and one or more modification which can include (ii) β2m null or low expression in comparison to its counterpart primary cell, (iii) knockout in one or both CD58 and CD54, (viii) deletion or reduced expression in at least one of a list of genes which includes NLRC5, TRAC, CIITA, TAP2, and RFXANK, and (ix) introduced or increased expression in at least one of a list of genes which includes HLA-E, in comparison to it counterpart primary cell.
Valamehr fails to state explicitly using a CAR-T cell and using a CRISPR-Cas system comprising sgRNAs of SEQ ID NO: 94 and SEQ ID NO: 95 of instant claim 1 and the cells being derived from a healthy donor of instant claim 28.
Morgan, however, in regards to claim 1 teaches that T cells have significant anti-cancer immune activity (pg.2 col 1, lines 32-36) and CAR-T cells have been efficacy in liquid tumors and are showing promising results in solid tumors (pg.2, col 2, lines 1-6), further Morgan teaches T cells engineered to express CARs have amplified cytotoxic activity (pg.2, col 2, lines 50-55).
In regards to claim 28 Morgan teaches that cells derived from diseased patients (autologous) may be adversely affected in heavily pre-treated patients so that the quality and number of cells for ex vivo modification and donor cells (allogenic) cells lower the risk of genetically modifying and re-infusing leukemic cells and can be prepared and stored for future use (pg.4 col 1, lines 3-15).
Morgan fails to teach using a CRISPR-Cas system comprising sgRNAs of SEQ ID NO: 94 and SEQ ID NO: 95 of instant claim 1.
Meissner, however, teaches using a CRISPR system to reduce or knockout expression of MHC-I and/or MHC-II gene to develop universal donor stem cells (column 1, lines 48-57). Further, Messiner teaches the gRNA sequences which can knockout RFX5 (col. 32, line 42 – col. 33, line 43), of which SEQ ID NO: 87101 is identical to SEQ ID NO: 94 of the instant application. Meissner fails to teach the sgRNA of SEQ ID NO: 95.
Baumgartner, teaches the gRNA sequences which can target CD58 (pg.74, Table 6), of which SEQ ID NO: 1570 is identical to SEQ ID NO: 95 of the instant application.
Thus, Valamehr discloses all of the modification and embodiments claimed in the instant application as options to construct an engineered immune cell with impaired of reduced expression of RFX5 and CD58 and optionally NLRC5 relative to a cell without genomic modification, Morgan teaches the success of CAR-T cells in the treatment of liquid and solid tumors and further teaches healthy donor obtained primary cells as a beneficial option, and Meissner and Baumgartner teach gene knockout using CRISPR-Cas systems with sgRNA of the claims SEQ ID NO:94 and SEQ ID NO: 95, respectively. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try combinations of the teachings of Valamehr informed by the teachings of Morgan, Meissner, and Baumgartner with a reasonable expectation of success to develop a CAR-T cell with knocked out expression of RFX5 and CD58 and optionally NLRC5 by CRISPR directed sgRNAs to develop a universal CAR-T cells which are an effective cytotoxic treatment against tumors.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims are 1, 15, 18, 28, 56, and 57 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 4, 5, 6, 11, 14, 15, 19, and 29-31 of U.S. Patent No. 12,577,283 in view of Valamehr et al., Morgan et al., Meissner et al., and Baumgartner et al.
Claim 1 of the US Patent which depends on claim 1 recites claim to an engineered immune cell made by functionally reducing RFX5 gene expression with a CRISPR/Cas System using an sgRNA comprising SEQ ID NO: 4 wherein the cell exhibits a reduced level of expression of an MHC class I protein and MHC class II protein at the cell surface. This significantly overlaps with instant claim 22.
Claim 3 of the US patent which depends on claim 1 further recites the engineered to have reduced expression of one or more of the genes NLRC5, TAP2, B2m, TRAC, RFXAP, CIITA, and RFXANK. This significantly overlaps with instant claims 15 and 18.
Claim 4 of the US patent which depends on claim 1 further recites the immune cell is a T cell. This significantly overlaps with instant claim 1.
Claim 6 of the US patent which depends on claims 5 and 1 further recites the immune cell expressing an antigen binding protein (claim 5) which is either a T cell receptor (TCR) or chimeric antigen receptor (CAR) (claim 6). This significantly overlaps with claim 1.
Claim 15 of the US Patent which depends on claims 14, 11, and 1 further recites the cells expresses on or both of TAP2 or NLRC5 are reduced in expression (claim 11), and the cell is expressing and antigen binding protein (claim 14) which is either a TCR or CAR (claim 15). This claim significantly overlaps with instant claim 15.
Claim 19 of the US patent which depends on claim 1 further recites the immune cell is obtained from a healthy volunteer or derived from and iPSC. This significantly overlaps with claim 28.
Claim 30 of the US patent which depends on claim 1 further recites a pharmaceutical composition containing the engineered immune cell (claim 29), and wherein the engineered immune cell further expresses one or more additional protein from a list of proteins. This significantly overlaps with instant claim 56.
Claim 31 of the US patent recites claim to a method treating a condition by administering the engineered immune cell to the patient. This significantly overlap with instant claim 57.
The US patent fails to teach the reduced expression of CD58 as well as the sgRNA sequences of instant claim 1, and further for some embodiments fails to teach the engineered immune cell being a CAR-T cell.
Valamehr, however, teaches a derivative effector cell (defined in the specification as including, immune cells (page 50, paragraph 000159) comprising a CAR. Valamehr further discusses CD58 knockout reduces allogenic NK cells activation (pg.63, lines 6-7).
Valamehr fails to state explicitly using a CAR-T cell and using a CRISPR-Cas system comprising sgRNAs of SEQ ID NO: 94 and SEQ ID NO: 95 of instant claim 1.
Morgan, however, teaches that T cells have significant anti-cancer immune activity (pg.2 col 1, lines 32-36) and CAR-T cells have been efficacy in liquid tumors and are showing promising results in solid tumors (pg.2, col 2, lines 1-6), further Morgan teaches T cells engineered to express CARs have amplified cytotoxic activity (pg.2, col 2, lines 50-55).
Morgan fails to teach using a CRISPR-Cas system comprising sgRNAs of SEQ ID NO: 94 and SEQ ID NO: 95 of instant claim 1.
Meissner, however, teaches using a CRISPR system to reduce or knockout expression of MHC-I and/or MHC-II gene to develop universal donor stem cells (column 1, lines 48-57). Further, Messiner teaches the gRNA sequences which can knockout RFX5 (col. 32, line 42 – col. 33, line 43), of which SEQ ID NO: 87101 is identical to SEQ ID NO: 94 of the instant application. Meissner fails to teach the sgRNA of SEQ ID NO: 95.
Baumgartner, teaches the gRNA sequences which can target CD58 (pg.74, Table 6), of which SEQ ID NO: 1570 is identical to SEQ ID NO: 95 of the instant application.
Thus, the US patent recites claim to an engineered immune cell with reduced RFX5 expression and embodiments which significantly encompass the instant claims, and Valamehr teaches knocking down CD58 to reduced allogeneic NK cell activation, Morgan highlights the success and cytotoxic activity of CAR-T cells for the treatment of cancer, and Meissner and Baumgartner teach guide RNAs for knocking out gene expression and the specific sequences of the instant application. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention in possession of the US Patent would have found it obvious to combine the teachings of the US patent with Valamehr, Morgan, Meissner, and Baumgartner with a reasonable expectation of success to reach the claimed invention.
Response to Arguments
Applicant's arguments filed 11 May 2026 have been fully considered but they are not persuasive.
In response to applicant’s arguments stating there is no prima facie case of obviousness because “Valamehr does not supply any sequences for editing genes encoding RFX5 or CD58 and Morgan does not fill the gap” (remarks (5/11/2026), pg.4, “claim rejections under 35 U.S.C. 103”, paragraph 2) and “The art contained no defined solutions, and the art is sufficiently unpredictable to form any expectation of success in any embodiment, such as on in claim 1” (remarks (5/11/2026), pg.5, “claim rejections under 35 U.S.C. 103”, paragraph 1) with respect to claim 1 has been considered but is not persuasive because of the modified grounds of rejection which encompasses the new limitations of the claim 1 amendment to include sequences.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. CHENG HSIN YUAN ET AL: "Generation of hypoimmunogenic allogeneic CART cells by inactivation of transcriptional regulators of HLA Class I and II genes", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 10, no. Suppl. 2, 210, 7 November 2022. (of IDS 22 Feb 2024) appears to be related to the instant application. This document discloses the reduced express or knockdown of NRLC5, RFX5 and 2m using CRISPR/Cas9 to develop autologous CAR T cells which is disclosed in the instant application. The document was published after the effectively filed date. It is not prior art against the claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647
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